JPWO2009004900A1 - Ubiquinone-containing immune adjuvant - Google Patents

Abstract

The present invention relates to an immune adjuvant having an excellent antibody production enhancement function and high safety, and a vaccine composition containing the same. More specifically, the present invention relates to an immunoadjuvant comprising a ubiquinone represented by the formula (I) and a vaccine composition thereof. [Chemical 1]

Description

Background of the Invention

FIELD OF THE INVENTION The present invention relates to an immunoadjuvant comprising ubiquinone and a vaccine composition comprising the same.

BACKGROUND ART It is known that antigenic substances such as foreign proteins and polysaccharides are inoculated into living bodies as vaccines in the treatment or prevention of infectious diseases and the like. However, it is often problematic that the amount of antibody production in the body caused by the antigenic substance does not reach a sufficient level from the viewpoint of the body's defense against diseases.

For the purpose of enhancing the immunogenicity of vaccines, immunoadjuvants that are administered to living bodies together with antigenic substances have been developed.
Conventional immune adjuvants include, for example, Freund's adjuvant, aluminum salt (alum), virosome, exotoxin, MF59, saponin, LPS, cytokine, CpG oligonucleotide and the like (Expert. Rev. Vaccine, Vol. 2 (2), 167-188 (2003)). However, these conventional immunoadjuvants cause serious side effects, or the immunopotentiating action is not sufficient, and applicable diseases are limited.

In addition, transdermal vaccines are said to significantly increase the production of IgG antibodies in the blood and are useful in the treatment or prevention of infectious diseases and the like. However, the protective ability of a transdermal vaccine in the mucosa, which is the entrance of a pathogen, is generally low, and an adjuvant for transdermal administration that compensates for this is needed. As a conventional adjuvant suitable for transdermal administration, for example, cholera toxin and the like have been reported (Vaccine, Vol. 23, 2511-2519 (2005), Vaccine, Vol. 24, 6110-6119 (2006)). However, while cholera toxin has an adjuvant effect in animal experiments, it has not been observed in clinical trials to induce a sufficient level of immune response.
Therefore, it can still be desired to create an excellent novel immune adjuvant having a function of effectively increasing antibody production in a living body and having high safety, and a vaccine composition using the same.

Summary of the Invention

The present inventors have now found that a specific ubiquinone coenzyme can be used as an excellent immune adjuvant having a function of effectively increasing antibody production against an antigenic substance.
The present invention is based on such knowledge.
Therefore, an object of the present invention is to provide an excellent novel immunoadjuvant capable of effectively increasing antibody production and a vaccine composition containing the same.

（式中、ｎは１〜１０である）。
また、本発明によるワクチン組成物は、式（Ｉ）で表されるユビキノンと、抗原物質とを含んでなることを特徴とする。The immune adjuvant according to the present invention comprises ubiquinone represented by the formula (I):

(Wherein n is 1-10).
The vaccine composition according to the present invention comprises ubiquinone represented by the formula (I) and an antigen substance.

  The immune adjuvant according to the present invention has a function of remarkably increasing antibody production against an antigenic substance in a living body, and can be advantageously used in the treatment or prevention by immunity of various diseases.

The measurement result of the amount of antibody production by ELISA at the time of using the immunoadjuvant (CoQ10) by this invention is shown. As a reference example, the measurement results of antibody production by ELISA when cholera toxin is used or when no immune adjuvant is used are shown. The IgG1 / IgG2a value in the blood sample when the immunoadjuvant according to the present invention is used is shown. In addition, as reference examples, IgG1 / IgG2a values in blood samples when cholera toxin is used or when no immune adjuvant is used are shown. The measurement result of the antibody production amount by ELISA at the time of using the immune adjuvant (CoQ2, CoQ4, CoQ6, or CoQ10) by this invention is shown. In addition, as a reference example, measurement results of antibody production by ELISA in the absence of immune adjuvant are shown.

DETAILED DESCRIPTION OF THE INVENTION

Definitions As used herein, “immunological adjuvant” means a substance that, when administered to a living body together with an antigenic substance, increases the immune response to the antigenic substance.

In the present specification, the “peptide having functionally equivalent activity” refers to the following.
In addition to polymorphisms and mutations in the gene that encodes the peptide, there are mutations such as amino acid substitutions, deletions or additions in the amino acid sequence in vivo, by modification reactions during purification, or by artificial manipulation. Nonetheless, it is known that there are nonetheless exhibiting substantially the same physiological and biological activity as peptides without mutations. Thus, even if there is a structural difference, a peptide that has no significant difference in function is referred to as a “functionally equivalent peptide”.

  Further, in the present specification, “treatment” means improving an established disease state, and “prevention” means preventing establishment of a disease state in the future.

  In the present specification, “histone H1-like antigen” means an antigen that is recognized on the cell membrane of splenocytes by a monoclonal antibody produced by hybridoma 1F5, hybridoma 3F2, hybridoma 15F11, hybridoma 17C2, or hybridoma 16G9. . Here, the hybridoma 1F5, the hybridoma 3F2, the hybridoma 15F11, the hybridoma 17C2 or the hybridoma 16G9 has an original deposit date of August 19, 2004. The National Institute of Advanced Industrial Science and Technology, Patent Biology Center (address: Ibaraki, Japan) Tsukuba City East 1-1-1 Chuo No. 6), with accession number FERM BP-10409, accession number FERM BP-10410, accession number FERM BP-10411, accession number FERM BP-10413 or accession number FERM BP-10413 It is deposited with.

Immunoadjuvant As described above, the immunoadjuvant according to the present invention comprises ubiquinone represented by the formula (I).
It is known that the ubiquinone represented by the formula (I) can play an important role in supplying energy necessary for various cellular activities by being involved in the electron transport system. When the above ubiquinone is used as an immunoadjuvant, it is a surprising fact that Th2 cells can induce humoral immunity in a dominant state and effectively increase antibody production. According to the present invention, it is possible to effectively increase antibody production using such ubiquinone as an immune adjuvant.

  In the ubiquinone represented by the formula (I), n is preferably 2 to 10, more preferably 6 to 10, and further preferably 10. Such ubiquinone is present as a coenzyme in the living organisms of lower animals and higher animals, and thus can be advantageously used as a safe immune adjuvant.

  Moreover, the immunoadjuvant according to the present invention may contain other components as long as the effect of ubiquinone antibody production increase is not hindered. Such other components include, for example, binders, colorants, desiccants, preservatives, wetting agents, stabilizers, excipients, adhesives, plasticizers, tackifiers, thickeners, patch materials, ointment bases. Materials, exfoliants, basic substances, absorption promoters, fatty acids, fatty acid esters, higher alcohols, surfactants, water, buffering agents, etc., preferably buffering agents, ointment bases, fatty acids, preservatives, Basic substance or surfactant.

  The content of ubiquinone in the immune adjuvant according to the present invention may be appropriately determined in consideration of the nature of the antigenic substance used, the required amount of antibody production, the dosage form, etc., for example, 1 to 100% by weight. . The immune adjuvant according to the present invention is produced by appropriately mixing ubiquinone and various components as described above.

  In addition, the above-described effects of the ubiquinone represented by the formula (I) as an immunoadjuvant are particularly advantageous when used together with a transdermal vaccine for the prevention or treatment of various diseases. Therefore, the immune adjuvant according to the present invention is preferably used as an adjuvant for transdermal administration.

Vaccine Composition The immunoadjuvant according to the present invention may be administered separately from the antigenic substance when administered to a living body, but can be administered together with the antigenic substance as a vaccine composition.

  The antigenic substance in the vaccine composition may be appropriately selected according to the target disease, the nature of the patient, etc., and is not particularly limited as long as it can induce an immune response together with ubiquinone. Preferred examples include peptides, proteins ( Glycoprotein, lipoprotein, etc.), carbohydrate (polysaccharide, etc.), lipid (glycolipid, etc.), nucleic acid (oligonucleotide, single-stranded DNA, double-stranded DNA, RNA, plasmid DNA, etc.), or toxoid. Is preferably a peptide or protein.

  The antigenic substance may be naturally derived, or may be produced by chemical synthesis or DNA recombination technology. Such antigenic substances include virus-derived antigens (recombinant viruses, virus lysates, virus analogs such as virosome), bacteria-derived antigens (bacterial lysates, etc.), cancer-related antigens (cancer cell lysates, etc.), etc. Is mentioned.

  Moreover, the above-mentioned antigenic substance may be used in combination of a plurality of types, and the present invention includes such an embodiment. In addition, the vaccine composition according to the present invention can be used for treatment or prevention of various diseases depending on the type and nature of the antigenic substance. When the antigenic substance that can induce the production of an antibody having immunosuppressive activity is used, the vaccine composition according to the present invention is advantageous in preventing or treating transplant rejection in a living body, particularly an organ transplant patient. Therefore, according to another preferred embodiment of the present invention, the vaccine composition is used for the prevention or treatment of transplant rejection.

And according to a preferred embodiment of the present invention, the antigenic substance comprises a peptide selected from the following (a) and (b):
(A) a peptide comprising the amino acid sequence represented by SSVLYGGPPSAA (SEQ ID NO: 1),
(B) a peptide consisting of an amino acid sequence represented by SSVLYGGPPSAA (SEQ ID NO: 1), wherein one or several amino acids are substituted, deleted or added, and the peptide according to (a) above A peptide having functionally equivalent activity.
The antigenic substance is particularly advantageous in inducing the production of antibodies having immunosuppressive activity in the living body.

  Moreover, in the peptide as described in said (b), the range of "1 or several" Preferably means 1-3, More preferably, it is about 1-2.

  Whether or not the peptide described in (b) above has a functionally equivalent activity to the peptide described in (a) can be confirmed, for example, by determining the amount of antibody produced by administration of the peptide to a living body by ELISA, etc. And a known assay method such as a method of comparing the immunosuppressive function of the antibody by a mixed lymphocyte reaction (MLR reaction).

Examples of suitable antigenic substances that can induce the production of antibodies having immunosuppressive activity in addition to the above peptides include histone H1, histone H1-like antigen, NYQTYTPRPPHS (SEQ ID NO: 2), VTNNQTSPRWEI (SEQ ID NO: 3), WKPVSLTLHTHP (SEQ ID NO: 4) or a peptide consisting of the amino acid sequence represented by HATGTHGLSLSH (SEQ ID NO: 5), a peptide analog having a functionally equivalent activity to the peptide, a complex or a mixture containing these, and the like Can be mentioned. Examples of the peptide analog include peptide analogs having substitutions, deletions or additions as described in (b) above.
The details of the above-described antigenic substance and the assay method thereof are described in WO 2006/205580 by the present inventors, and the contents of this document are incorporated herein by reference.

  According to a preferred embodiment of the present invention, the vaccine composition further comprises a pharmaceutically acceptable carrier. In addition, when the antigenic substance has a low molecular weight, it is particularly advantageous to administer a complex in which a carrier and the antigenic substance are bound to a living body in order to effectively induce an immune response. Therefore, according to a more preferred embodiment of the present invention, the carrier is bound to an antigen substance. The carrier is preferably keyhole limpet hemocyanin (KLH), ovalbumin (OVA) or bovine serum albumin (BSA), more preferably KLH. .

  According to a further preferred aspect of the present invention, the antigenic substance is a conjugate of the polypeptide described in (a) or (b) above and a carrier selected from KLH, OVA and BSA. According to a further preferred embodiment, the antigen substance is a conjugate of the polypeptide described in (a) or (b) above and KLH. According to another preferred embodiment, the antigenic substance is a conjugate of histone H1 or histone H1-like antibody and a carrier selected from KLH, OVA and BSA.

  In the case of artificially synthesizing the above antigenic substance, it is possible to use a known peptide synthesis technique such as a peptide solid phase synthesis method or a peptide liquid phase synthesis method. The method for binding the antigenic substance to the carrier is not particularly limited as long as it does not interfere with the immunogenicity of the antigenic substance. For example, EDC (Ethylenedichloride), DCC (dicyclohexyl carbodiimide), DIC (1,3-diisopropyl) Examples include a method of binding an antigenic substance and a carrier using a dehydration condensation agent such as carbodiimide), a crosslinking agent such as glutaraldehyde, maleimide, maleimide benzoyloxysuccinic acid, or a linker such as PEG or a linker peptide. And according to the preferable aspect of this invention, the antigenic substance and the said support | carrier are couple | bonded through carbodiimide or glutaraldehyde. For a method for producing such a conjugate of a peptide and a carrier, see, for example, the method described in “Basics and Experiments of Peptide Synthesis” by Nobuo Izumiya et al.

  Moreover, the vaccine composition by this invention may further contain the said other component. Suitable examples of such other components include superantigens, cytokines, cholera toxin or variants thereof, heat-labile enterotoxins or variants thereof, and CpG oligonucleotides. The addition of the above components is advantageous for further enhancing the function as an immunogen of the antigen substance.

Further, the amount of the antigenic substance in the vaccine composition according to the present invention is not particularly limited as long as it is an immunologically effective amount for the target disease, but the specific amount of such an antigenic substance is set according to the age and weight of the living body. Depending on the nature and progress of the disease, it is appropriately performed by a person skilled in the art such as a doctor. And the quantity of the antigenic substance in the said vaccine composition can be 1-50 weight%, for example.
In addition, the amount of the immune adjuvant in the vaccine composition may also be appropriately determined by those skilled in the art, taking into account the effective amount that enhances the immune response to the antigenic substance in the living body, using the amount of antibody production in the living body as an index, for example, 1 to 50% by weight.

Uses The vaccine composition as described above can be prepared by a known method in the field of pharmaceutical technology, for example, solution, suspension, ointment, powder, lotion, W / O emulsion, O / W emulsion, emulsion, cream. , Prepared in the form of a patch, patch, gel, etc., and preferably used as a medicine. Therefore, according to another aspect of the present invention, there is provided a pharmaceutical composition comprising the above vaccine composition. The vaccine composition according to the present invention can significantly induce antibody production when administered transdermally. Therefore, according to another preferred embodiment of the present invention, the vaccine composition is provided in the form of a transdermally absorbable preparation.

  Further, as described above, ubiquinone in the present invention can be administered to a living body as a vaccine composition together with an antigenic substance or as an immunoadjuvant of a preparation different from the antigenic substance, and can significantly increase the amount of antibody production in the living body. Therefore, according to another aspect of the present invention, there is provided a method for increasing the amount of antibody production in a living body against an antigenic substance, comprising an immunologically effective amount of the antigenic substance and an effective amount of formula (I) as an immune adjuvant. There is provided a method comprising administering the represented ubiquinone simultaneously or sequentially to a living body.

  In addition, when an immune adjuvant according to the present invention and an antigenic substance capable of inducing production of an antibody having immunosuppressive activity are administered to a living body, it is possible to effectively treat or prevent transplant rejection. Therefore, according to another aspect of the present invention, there is provided a method for suppressing transplant rejection in a living body, which is represented by an immunologically effective amount of the above antigenic substance and an effective amount of formula (I) as an immunoadjuvant. There is provided a method comprising administering ubiquinone simultaneously or sequentially to a living body. The antigenic substance in the above method is the same as the antigenic substance that can induce the production of an antibody having immunosuppressive activity in the vaccine composition.

  The effective amount of ubiquinone as an immunoadjuvant and the immunologically effective amount of an antigenic substance are determined according to the type and nature of the antibody substance, the biological species, age and weight and condition, the type of disease, the timing of administration, the administration method, etc. In consideration, it is further determined appropriately by those skilled in the art using the amount of antibody against the antigenic substance in the living body as an index.

  In addition, the method for administering the antigenic substance, immunoadjuvant or vaccine composition of the present invention to a living body can be appropriately selected according to the patient's condition, the nature of the disease, etc., for example, intraperitoneal administration, subcutaneous injection, intradermal Examples include transdermal administration such as injection and sticking, nasal administration, oral administration, transmucosal administration (rectal, vaginal administration, transcorneal administration, etc.), and preferably transdermal administration. Other methods include a method in which immunocompetent cells, an immunoadjuvant, an antigenic substance, and the like are mixed outside the body and then administered to a living body to stimulate an immune reaction in the body. Examples of the immunocompetent cells include antigen-presenting cells such as Langerhans cells and tree cells.

  Yet another aspect of the present invention provides the use of ubiquinone in the manufacture of an immune adjuvant. According to still another aspect of the present invention, use of a combination of an immunological adjuvant containing ubiquinone and an antigenic substance capable of inducing production of an antibody having immunosuppressive activity in the manufacture of an agent for treating or preventing transplant rejection in a living body Is provided.

  Moreover, the living body in the present invention is preferably a mammal, more preferably a human, cow, pig, horse, sheep, dog or cat, more preferably a human.

EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.
Test Example 1: Confirmation of increase in antibody production by immune adjuvant 1
In order to confirm the amount of antibody produced when ubiquinone represented by the formula (I) (n = 10, coenzyme Q10) was administered together with the antigenic substance, a test was performed according to the following procedure. In addition, as a reference example in the test, a case where only the antigenic substance was administered and a case where the antigenic substance and cholera toxin which is a mucosal immune adjuvant were administered together were selected.

Preparation of antigenic substance and immune adjuvant As the antigenic substance, a mixture of a peptide having the amino acid sequence represented by SEQ ID NO: 1 and a complex of the peptide and KLH was used.
In the preparation of the antigen substance, first, a peptide having the amino acid sequence represented by SEQ ID NO: 1 was synthesized by Fmoc peptide solid phase synthesis method (manufacturing apparatus; manufactured by ABI430 type Applied Biosystems). Further, the complex of the above peptide and KLH (manufactured by SIGMA) was prepared by adding 5 mg of the above peptide, about 20 mg of KLH and 30 μg of glutaraldehyde (Katayama Chemical Co., Ltd.) in a phosphate buffer (pH 8.0) for about 6 hours at room temperature. Synthesized with stirring.
Next, 10 μg each of the peptide and the complex were mixed in PBS to obtain an antigenic substance (10 μg peptide, 10 μg complex / 0.2 mL PBS).
Moreover, coenzyme Q10 (manufactured by SIGMA) was prepared as an immune adjuvant.
Further, cholera toxin (manufactured by SIGMA) was used as an adjuvant as a reference example.

Moreover, the antigenic substance and the immunoadjuvant were used for the following tests as a tape preparation in the following procedure.
First, an antigen substance (20 μg), coenzyme Q10 (20 mg), and a water-soluble ointment base material (macrogol 4000: macrogol 1500: propylene glycol = 3: 1: 1. Here, macrogol 1500 is This is a mixture of equal amounts of Macrogol 1540 and Macrogol 300.). Next, 100 mg of the mixture was applied to a patch test tape (patch test adhesive bandage, Torii) to obtain a tape preparation.

Immunity
Antigen (10 μg peptide, 10 μg complex / 0.1 mL PBS) was intraperitoneally administered to Balb / c mice (female, 4 weeks old, n = 4, manufactured by Oriental Yeast).
Next, at 2 and 4 weeks after the intraperitoneal administration, the tape preparation was affixed to mice for 72 hours to administer the antigenic substance and immune adjuvant transdermally. In addition, in the application site | part of the said tape formulation, shaving and complete hair removal by the hair removal cream (brand name Epilat, Kanebo Co., Ltd.) were performed beforehand. Further, the skin was dried for 1-2 hours, and the keratin was removed by tape stripping.
Blood samples from each mouse were collected at the time of antigenic substance administration, about one week after application of the tape preparation, and on the 25th day from the start of the test.

Measurement of antibody production by ELISA Each blood sample was collected from each mouse, and then the amount of antibody in mouse serum was measured by ELISA according to the following procedure. In the following, OVA-SSV is a complex of ovalbumin and a peptide having the amino acid sequence represented by SEQ ID NO: 1, and OVA-SSV is obtained by a method similar to that of the above peptide and KLH complex. Synthesized.
First, a histone H1 solution (20 μg / mL, manufactured by Roche) or an OVA-SSV solution (OVA-SSV: 0.387 mg / mL, solvent: 0.02 M phosphate buffer, 0.9% NaCl, pH 8.0) was added to 0.1 M NaHCO 3 ( Prepared with pH 9.3) solution. Next, 50 μL of each of the obtained solutions was added to each well of a 96-well plate and allowed to stand at room temperature for 1 hour. Next, each well was washed three times with PBST, and then 150 μL of PBS solution (3% milk, 1% BSA-containing PBS solution) was added to each well and incubated at 37 ° C. for 1 hour. Next, each well was washed three times with PBST, and then 50 μL of mouse serum diluted 1000-fold with PBST was added to the well and allowed to stand at room temperature for 1 hour. Next, each well was washed three times with PBST, and then 50 μL of peroxidase-labeled mouse IgG (SIGMA) diluted 2000 to 4000 times with PBST was added to the well and left at room temperature for 1 hour. Next, after washing each well 3 times with PBST, ABTS (2,2'-azino-bis [3-ethylbenzoline-6-sulfonate], manufactured by SIGMA) is added as a chromogenic substrate and incubated for 30 to 60 minutes. did. Thereafter, the absorbance of each well was measured by Multiscan Ascent (manufactured by Thermo Labsystems, wavelength 405 nm).

As a result, the mean absorbance ± standard error of the serum samples on the 25th day from the start of the test of each group were as shown in FIG.
The average value ± standard error of the absorbance of the measurement sample is 0.670 ± 0.033 when the antigenic substance is transdermally administered with coenzyme Q10, and 0.355 ± 0 when the antigenic substance alone is transdermally administered. 0.062, and 0.551 ± 0.202 when the antigenic substance was administered transdermally with cholera toxin. It was confirmed that the amount of antibody produced when coenzyme Q10 was used as an immunoadjuvant was higher than when the antigen substance alone was administered or when cholera toxin was used as the immunoadjuvant.

Test Example 2: Measurement of IgG1 / IgG2 ratio A blood sample collected on the 25th day from the start of the test was used to measure the IgG1 / IgG2 ratio as an index of the Th2 / Th1 balance.
In addition, as a blood sample for comparison, a sample obtained by inoculating only the antigenic substance by intraperitoneal administration instead of transdermal administration at the same point in the dosing schedule of Test 1 was used.
The IgG1 / IgG2 ratio was measured using a Mouse Monoclonal Antibody Isotyping Reagents kit (SIGMA).
Specifically, first, 100 μL of a solution obtained by diluting mouse serum 1000 times with PBS was added to the wells in the plate and incubated at 37 ° C. for 1 hour. Next, each well was washed three times with PBS, and then 100 μL of isotyping specific reagents (IgA, IgG1, IgG2a, IgG2b-containing reagent) diluted 1000 times were added to each well and incubated at room temperature for 30 minutes. Next, each well was washed three times with PBST, and then 100 μL of peroxidase-labeled mouse IgG (manufactured by SIGMA) diluted 5000 times with PBST was added to the well and allowed to stand at room temperature for 1 hour. Next, after each well was washed 3 times with PBST, ABTS was added as a chromogenic substrate and incubated for 5-10 minutes. Thereafter, the absorbance of each well was measured by Multiscan Ascent (manufactured by Thermo Labsystems, wavelength 405 nm).

As a result, the absorbance of each group measurement sample was as shown in FIG.
The average absorbance of the measurement sample is 2.28 when the antigenic substance is administered transdermally with coenzyme Q10, and 1.33 when the antigenic substance alone is administered intraperitoneally, and the antigenic substance is administered transdermally with cholera toxin. It was 1.46. When coenzyme Q10 was used as an immunoadjuvant, it was observed that the IgG1 / IgG2 ratio was higher than when only the antigenic substance was administered intraperitoneally or when cholera toxin was used as the immunoadjuvant. From this IgG1 / IgG2 ratio data, when Coenzyme Q10 was used as an immunoadjuvant, Th2 cells were in a predominant state compared to the case where only the antigenic substance was administered intraperitoneally or cholera toxin was used as the immunoadjuvant. It was confirmed that humoral immunity was induced.

Test Example 3: Confirmation of increase in antibody production by immune adjuvant 2
Coenzyme Q2 (n = 2; CoQ2), coenzyme Q4 (n = 4; CoQ4), coenzyme Q6 (n = 6; CoQ6) or coenzyme Q10 (n = 10; CoQ10) was treated with the same procedure as in Test Example The antibody was administered together with the substance, and the antibody production in the mouse was confirmed by ELISA. As a reference example in the test, the case where only the antigenic substance was administered was selected.

As a result, the average value of the absorbance of the serum samples on the 25th day from the start of the test in each group was as shown in FIG.
It was observed that the amount of antibody production was higher when coenzyme Q2, Q4, Q6 or Q10 was administered together with the antigenic substance than when only the antigenic substance was administered.
In addition, the group using a compound having a long side chain (n in the compound represented by the formula (I)) as an adjuvant showed a higher antibody production amount.

Claims (23)

An immunoadjuvant comprising a ubiquinone represented by formula (I):

(Wherein n is 1-10).   The immune adjuvant according to claim 1, wherein n is 6 to 10.   The immune adjuvant according to claim 2, wherein n is 10.   The immunoadjuvant of claim 1 for transdermal administration.   A vaccine composition comprising the immunoadjuvant of claim 1 and an antigenic substance.   The vaccine composition according to claim 5, wherein the antigenic substance is selected from the group consisting of a virus-derived antigen, a bacterium-derived antigen, a cancer-associated antigen, or a combination thereof.   The vaccine composition according to claim 5, wherein the antigenic substance is selected from the group consisting of peptides, proteins, carbohydrates, lipids, nucleic acids, toxoids, and combinations thereof.   The vaccine composition according to claim 7, wherein the antigenic substance is a peptide or a protein. The vaccine composition according to claim 5, wherein the antigenic substance comprises a peptide selected from the following (a) and (b):
(A) a peptide comprising the amino acid sequence represented by SEQ ID NO: 1,
(B) a polypeptide comprising an amino acid sequence in which one or several amino acids are substituted, deleted, or added in the amino acid sequence represented by SEQ ID NO: 1, wherein the polypeptide is functional with the peptide described in (a) A peptide that is equivalent to   6. The vaccine composition according to claim 5, further comprising a pharmaceutically acceptable carrier.   The vaccine composition according to claim 10, wherein the carrier is bound to an antigenic substance.   The vaccine composition according to claim 10, wherein the carrier is keyhole limpet hemocyanin, ovalbumin or bovine serum albumin.   The vaccine composition according to claim 12, wherein the carrier is keyhole limpet hemocyanin.   The vaccine composition according to claim 5, further comprising a component selected from the group consisting of superantigen, cytokine, cholera toxin and variants thereof, heat-labile enterotoxin and variants thereof and CpG oligonucleotides.   The vaccine composition according to claim 9, which is used for treatment or prevention of transplant rejection in a living body.   The vaccine composition according to claim 5, which is used as a medicine.   The vaccine composition according to claim 16, which is in the form of a transdermally absorbable preparation. A method for increasing the amount of antibody production in a living body against an antigenic substance, wherein an immunologically effective amount of the antigenic substance and an effective amount of ubiquinone represented by formula (I) as an immunoadjuvant are simultaneously or sequentially Comprising administering to:

(Wherein n is 1-10).   The method of claim 18, wherein n is 6-10.   The method of claim 19, wherein n is 10. A method for suppressing transplant rejection in a living body, wherein an immunologically effective amount of the antigenic substance according to claim 8 and an effective amount of ubiquinone represented by formula (I) as an immunoadjuvant are simultaneously or sequentially used. Comprising administering to a living body:

(Wherein n is 1-10).   The method of claim 21, wherein n is 6-10.   23. The method of claim 22, wherein n is 10.

Images